A Phase I Clinical Trial of Intrahepatic Artery Delivery of TG6002 in Combination with Oral 5-Fluorocytosine in Patients with Liver-Dominant Metastatic Colorectal Cancer.
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ICR Authors
Authors
West, EJ
Sadoun, A
Bendjama, K
Erbs, P
Smolenschi, C
Cassier, PA
de Baere, T
Sainte-Croix, S
Brandely, M
Melcher, AA
Ismail, F
Scott, KJ
Bennett, A
Banks, E
Gasior, E
Kent, S
Kurzawa, M
Hammond, C
Patel, JV
Collinson, FJ
Twelves, C
Anthoney, DA
Swinson, D
Samson, A
Sadoun, A
Bendjama, K
Erbs, P
Smolenschi, C
Cassier, PA
de Baere, T
Sainte-Croix, S
Brandely, M
Melcher, AA
Ismail, F
Scott, KJ
Bennett, A
Banks, E
Gasior, E
Kent, S
Kurzawa, M
Hammond, C
Patel, JV
Collinson, FJ
Twelves, C
Anthoney, DA
Swinson, D
Samson, A
Document Type
Journal Article
Date
2025-04-01
Date Accepted
2025-01-06
Abstract
PURPOSE: Effective treatment for patients with metastatic cancer is limited, particularly for those with colorectal cancer with metastatic liver lesions, in which accessibility to numerous tumors is essential for favorable clinical outcomes. Oncolytic viruses (OV) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoral administration routes. PATIENTS AND METHODS: We conducted a multicenter, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral prodrug 5-fluorocytosine to 15 patients with metastatic colorectal cancer. RESULTS: Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by the virus within tumor biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumor, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to the virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer antigens and neoantigens, with elevated functional activity, may be associated with improved anticancer activity. Despite these findings, no clinical efficacy was observed. CONCLUSIONS: In summary, these data demonstrate the delivery of OV to tumor via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data support the need for future studies using IHA administration of OVs.
Citation
Clinical Cancer Research, 2025, pp. OF1 - OF14
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Trans Immunotherapy